ID   VP4_ROTBC               Reviewed;         776 AA.
AC   P08713;
DT   01-JAN-1988, integrated into UniProtKB/Swiss-Prot.
DT   01-JAN-1988, sequence version 1.
DT   22-FEB-2023, entry version 119.
DE   RecName: Full=Outer capsid protein VP4 {ECO:0000255|HAMAP-Rule:MF_04132};
DE   AltName: Full=Hemagglutinin {ECO:0000255|HAMAP-Rule:MF_04132};
DE   Contains:
DE     RecName: Full=Outer capsid protein VP8* {ECO:0000255|HAMAP-Rule:MF_04132};
DE   Contains:
DE     RecName: Full=Outer capsid protein VP5* {ECO:0000255|HAMAP-Rule:MF_04132};
OS   Rotavirus A (strain RVA/Cow/Canada/C486/1977/G6P6[1]) (RV-A).
OC   Viruses; Riboviria; Orthornavirae; Duplornaviricota; Resentoviricetes;
OC   Reovirales; Sedoreoviridae; Rotavirus; Rotavirus A.
OX   NCBI_TaxID=10931;
OH   NCBI_TaxID=9913; Bos taurus (Bovine).
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=3035492; DOI=10.1093/nar/15.10.4361;
RA   Potter A.A., Cox G., Parker M., Babiuk L.A.;
RT   "The complete nucleotide sequence of bovine rotavirus C486 gene 4 cDNA.";
RL   Nucleic Acids Res. 15:4361-4361(1987).
CC   -!- FUNCTION: [Outer capsid protein VP4]: Spike-forming protein that
CC       mediates virion attachment to the host epithelial cell receptors and
CC       plays a major role in cell penetration, determination of host range
CC       restriction and virulence. Rotavirus attachment and entry into the host
CC       cell probably involves multiple sequential contacts between the outer
CC       capsid proteins VP4 and VP7, and the cell receptors. It is subsequently
CC       lost, together with VP7, following virus entry into the host cell.
CC       Following entry into the host cell, low intracellular or intravesicular
CC       Ca(2+) concentration probably causes the calcium-stabilized VP7 trimers
CC       to dissociate from the virion. This step is probably necessary for the
CC       membrane-disrupting entry step and the release of VP4, which is locked
CC       onto the virion by VP7. During the virus exit from the host cell, VP4
CC       seems to be required to target the newly formed virions to the host
CC       cell lipid rafts. {ECO:0000255|HAMAP-Rule:MF_04132}.
CC   -!- FUNCTION: [Outer capsid protein VP5*]: Forms the spike 'foot' and
CC       'body' and acts as a membrane permeabilization protein that mediates
CC       release of viral particles from endosomal compartments into the
CC       cytoplasm. During entry, the part of VP5* that protrudes from the virus
CC       folds back on itself and reorganizes from a local dimer to a trimer.
CC       This reorganization may be linked to membrane penetration by exposing
CC       VP5* hydrophobic region. In integrin-dependent strains, VP5* targets
CC       the integrin heterodimer ITGA2/ITGB1 for cell attachment.
CC       {ECO:0000255|HAMAP-Rule:MF_04132}.
CC   -!- FUNCTION: [Outer capsid protein VP8*]: Forms the head of the spikes and
CC       mediates the recognition of specific host cell surface glycans. It is
CC       the viral hemagglutinin and an important target of neutralizing
CC       antibodies. In sialic acid-dependent strains, VP8* binds to host cell
CC       sialic acid, most probably a ganglioside, providing the initial
CC       contact. In some other strains, VP8* mediates the attachment to histo-
CC       blood group antigens (HBGAs) for viral entry. {ECO:0000255|HAMAP-
CC       Rule:MF_04132}.
CC   -!- SUBUNIT: [Outer capsid protein VP4]: Homotrimer. VP4 adopts a dimeric
CC       appearance above the capsid surface, while forming a trimeric base
CC       anchored inside the capsid layer. Only hints of the third molecule are
CC       observed above the capsid surface. It probably performs a series of
CC       molecular rearrangements during viral entry. Prior to trypsin cleavage,
CC       it is flexible. The priming trypsin cleavage triggers its rearrangement
CC       into rigid spikes with approximate two-fold symmetry of their
CC       protruding parts. After an unknown second triggering event, cleaved VP4
CC       may undergo another rearrangement, in which two VP5* subunits fold back
CC       on themselves and join a third subunit to form a tightly associated
CC       trimer, shaped like a folded umbrella. Interacts with VP6. Interacts
CC       with VP7. {ECO:0000255|HAMAP-Rule:MF_04132}.
CC   -!- SUBUNIT: [Outer capsid protein VP5*]: Homotrimer. The trimer is coiled-
CC       coil stabilized by its C-terminus, however, its N-terminus, known as
CC       antigen domain or 'body', seems to be flexible allowing it to self-
CC       associate either as a dimer or a trimer. {ECO:0000255|HAMAP-
CC       Rule:MF_04132}.
CC   -!- SUBCELLULAR LOCATION: [Outer capsid protein VP4]: Virion
CC       {ECO:0000255|HAMAP-Rule:MF_04132}. Host rough endoplasmic reticulum
CC       {ECO:0000255|HAMAP-Rule:MF_04132}. Host cell membrane
CC       {ECO:0000255|HAMAP-Rule:MF_04132}. Host cytoplasm, host cytoskeleton
CC       {ECO:0000255|HAMAP-Rule:MF_04132}. Host endoplasmic reticulum-Golgi
CC       intermediate compartment {ECO:0000255|HAMAP-Rule:MF_04132}. Note=The
CC       outer layer contains 180 copies of VP4, grouped as 60 dimers. Immature
CC       double-layered particles assembled in the cytoplasm bud across the
CC       membrane of the endoplasmic reticulum, acquiring during this process a
CC       transient lipid membrane that is modified with the ER resident viral
CC       glycoproteins NSP4 and VP7; these enveloped particles also contain VP4.
CC       As the particles move towards the interior of the ER cisternae, the
CC       transient lipid membrane and the non-structural protein NSP4 are lost,
CC       while the virus surface proteins VP4 and VP7 rearrange to form the
CC       outermost virus protein layer, yielding mature infectious triple-
CC       layered particles. VP4 also seems to associate with lipid rafts of the
CC       host cell membrane probably for the exit of the virus from the infected
CC       cell by an alternate pathway. {ECO:0000255|HAMAP-Rule:MF_04132}.
CC   -!- SUBCELLULAR LOCATION: [Outer capsid protein VP8*]: Virion
CC       {ECO:0000255|HAMAP-Rule:MF_04132}. Note=Outer capsid protein.
CC       {ECO:0000255|HAMAP-Rule:MF_04132}.
CC   -!- SUBCELLULAR LOCATION: [Outer capsid protein VP5*]: Virion
CC       {ECO:0000255|HAMAP-Rule:MF_04132}. Note=Outer capsid protein.
CC       {ECO:0000255|HAMAP-Rule:MF_04132}.
CC   -!- DOMAIN: [Outer capsid protein VP4]: The VP4 spike is divided into a
CC       foot, a stalk and body, and a head. {ECO:0000255|HAMAP-Rule:MF_04132}.
CC   -!- PTM: [Outer capsid protein VP4]: Proteolytic cleavage by trypsin
CC       results in activation of VP4 functions and greatly increases
CC       infectivity. The penetration into the host cell is dependent on trypsin
CC       treatment of VP4. It produces two peptides, VP5* and VP8* that remain
CC       associated with the virion. Cleavage of VP4 by trypsin probably occurs
CC       in vivo in the lumen of the intestine prior to infection of
CC       enterocytes. Trypsin seems to be incorporated into the three-layered
CC       viral particles but remains inactive as long as the viral outer capsid
CC       is intact and would only be activated upon the solubilization of the
CC       latter. {ECO:0000255|HAMAP-Rule:MF_04132}.
CC   -!- MISCELLANEOUS: In group A rotaviruses, VP4 defines the P serotype.
CC       {ECO:0000255|HAMAP-Rule:MF_04132}.
CC   -!- MISCELLANEOUS: Some rotavirus strains are neuraminidase-sensitive and
CC       require sialic acid to attach to the cell surface. Some rotavirus
CC       strains are integrin-dependent. Some rotavirus strains depend on
CC       ganglioside for their entry into the host cell. Hsp70 also seems to be
CC       involved in the entry of some strains. {ECO:0000255|HAMAP-
CC       Rule:MF_04132}.
CC   -!- MISCELLANEOUS: This strain probably uses sialic acid to attach to the
CC       host cell. {ECO:0000255|HAMAP-Rule:MF_04132}.
CC   -!- SIMILARITY: Belongs to the rotavirus VP4 family. {ECO:0000255|HAMAP-
CC       Rule:MF_04132}.
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DR   EMBL; Y00127; CAA68325.1; -; mRNA.
DR   SMR; P08713; -.
DR   GO; GO:0044172; C:host cell endoplasmic reticulum-Golgi intermediate compartment; IEA:UniProtKB-SubCell.
DR   GO; GO:0020002; C:host cell plasma membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0044168; C:host cell rough endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR   GO; GO:0044163; C:host cytoskeleton; IEA:UniProtKB-SubCell.
DR   GO; GO:0016020; C:membrane; IEA:UniProtKB-KW.
DR   GO; GO:0039624; C:viral outer capsid; IEA:UniProtKB-UniRule.
DR   GO; GO:0039665; P:permeabilization of host organelle membrane involved in viral entry into host cell; IEA:UniProtKB-UniRule.
DR   GO; GO:0099008; P:viral entry via permeabilization of inner membrane; IEA:UniProtKB-KW.
DR   GO; GO:0019062; P:virion attachment to host cell; IEA:UniProtKB-UniRule.
DR   Gene3D; 1.20.5.170; -; 1.
DR   Gene3D; 2.60.120.200; -; 1.
DR   HAMAP; MF_04132; Rota_A_VP4; 1.
DR   HAMAP; MF_04125; Rota_VP4; 1.
DR   InterPro; IPR013320; ConA-like_dom_sf.
DR   InterPro; IPR042546; Rota_A_VP4.
DR   InterPro; IPR035330; Rota_VP4_MID.
DR   InterPro; IPR038017; Rota_VP4_MID_sf.
DR   InterPro; IPR000416; VP4_concanavalin-like.
DR   InterPro; IPR035329; VP4_helical.
DR   Pfam; PF17477; Rota_VP4_MID; 1.
DR   Pfam; PF00426; VP4_haemagglut; 1.
DR   Pfam; PF17478; VP4_helical; 1.
DR   SUPFAM; SSF49899; Concanavalin A-like lectins/glucanases; 1.
DR   SUPFAM; SSF111379; VP4 membrane interaction domain; 1.
PE   2: Evidence at transcript level;
KW   Capsid protein; Coiled coil; Disulfide bond; Hemagglutinin;
KW   Host cell membrane; Host cytoplasm; Host cytoskeleton;
KW   Host endoplasmic reticulum; Host membrane; Host-virus interaction;
KW   Membrane; Outer capsid protein; Viral attachment to host cell;
KW   Viral penetration into host cytoplasm;
KW   Viral penetration via permeabilization of host membrane; Virion;
KW   Virus entry into host cell.
FT   CHAIN           1..776
FT                   /note="Outer capsid protein VP4"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT                   /id="PRO_0000041024"
FT   CHAIN           1..231
FT                   /note="Outer capsid protein VP8*"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT                   /id="PRO_0000041025"
FT   CHAIN           248..776
FT                   /note="Outer capsid protein VP5*"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT                   /id="PRO_0000041026"
FT   REGION          65..224
FT                   /note="Spike head"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT   REGION          248..479
FT                   /note="Spike body and stalk (antigen domain)"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT   REGION          389..409
FT                   /note="Hydrophobic; possible role in virus entry into host
FT                   cell"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT   REGION          510..776
FT                   /note="Spike foot"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT   COILED          484..518
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT   MOTIF           308..310
FT                   /note="DGE motif; interaction with ITGA2/ITGB1 heterodimer"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT   MOTIF           448..450
FT                   /note="YGL motif; interaction with ITGA4"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT   MOTIF           644..646
FT                   /note="KID motif; interaction with HSPA8"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT   SITE            101
FT                   /note="Binding to sialic acid"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT   SITE            190
FT                   /note="Binding to sialic acid"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT   SITE            231..232
FT                   /note="Cleavage"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT   SITE            241..242
FT                   /note="Cleavage"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT   SITE            247..248
FT                   /note="Cleavage; associated with enhancement of
FT                   infectivity"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT   DISULFID        203..216
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
FT   DISULFID        318..380
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04132"
SQ   SEQUENCE   776 AA;  86769 MW;  69945BBA19CB5BBA CRC64;
     MASLIYRQLL TNSYTVELSD EIQEIGSTKT QNVTVNPGPF AQTNYASVNW GPGETNDSTT
     VEPVLDGPYQ PTTFNPPVSY WMLLAPTNAG VVDQGTNNTN RWLATILIKP NVQQVERTYT
     LFGQQVQVTV SNDSQTKWKF VDLSKQTQDG NYSQHGPLLS TPKLYGVMKH GGKIYTYNGE
     TPNATTGYYS TTNFDTVNMT AYCDFYIIPL AQEAKCTEYI NNGLPPIQNT RNIVPVSIVS
     RNIVYTRAQP NQDIVVSKTS LWKEMQYNRD IVIRFKFANS IIKSGGLGYK WSEVSFKPAN
     YQYTYTRDGE EVTAHTTCSV NGINDFNYNG GSLPTDFVIS KYEVIKENSF VYIDYWDDSQ
     AFRNMVYVRS LAADLNSVMC TGGDYSFAIP VGNYPVMTGG AVSLHSAGVT LSTQFTDFVS
     LNSLRFRFRL SVEEPPFSIL RTRVSGLYGL PAAKPNNSQE YYEIAGRFSL ISLVPSNDDY
     QTPIINSVTV RQDLERQLGE LRDEFNNLSQ QIAMSQLIDL ALLPLDMFSM FSGIKSTIDA
     AKSMATNVMK RFKKSSLANS VSTLTDSLSD AASSISRSAS VRSVSSTASA WTEVSNITSD
     INVTTSSIST QTSTISRRLR LKEMATQTDG MNFDDISAAV LKTKIDKSTQ LNTNTLPEIV
     TEASEKFIPN RAYRVIKDDE VLEASTDGKY FAYKVETILK RFHSMYKFAD LVTDSPVISA
     IIDFKTLKNL NDNYGISRQQ ALNLLRSDPR VLREFINQDN PIIRNRIESL IMQCRL
//